The identification of small organic molecules that affect specific biological functions has the potential to greatly impact both biology and medicine. Such molecules are useful not only as therapeutic agents and as probes of biological function. In but one example from the emerging field of chemical genetics, in which small molecules are used to alter the function of biological molecules to which they bind, these molecules have been useful at elucidating signal transduction pathways by acting as chemical protein knockouts, thereby causing a loss of protein function (Schreiber et al., J. Am. Chem. Soc., 1990, 112, 5583; Mitchison, Chem. and Biol., 1994, 1, 3). Additionally, due to the interaction of these small molecules with particular biological targets and their ability to affect specific biological function, they may also serve as candidates or leads for the development of new therapeutic agents. For example, natural products, which are small molecules obtained from nature, clearly have played an important role in advances in the fields of biology, chemistry, and medicine, serving as pharmaceutical leads, drugs (Newman et al., Nat. Prod. Rep. 2000, 17, 215-234), and powerful tools for studying cell biology (Schreiber, S. L. Chem. and Eng. News 1992 (October 26), 22-32).
One biological target of recent interest is histone deacetylase (see, for example, a discussion of the use of inhibitors of historic deacetylases in the treatment of cancer: Marks et al. Nature Reviews Cancer 2001, 1, 194; Johnstone et al. Nature Reviews Drug Discovery 2002, 1, 287). Post-translational modification of proteins (e.g., histones, transcription factors, tubulin) through the acetylation and deacetylation of lysine residues has a critical role in regulating their biological function. HDACs are zinc hydrolases that modulate gene expression through deacetylation of the N-acetyl-lysine residues of histone proteins and other transcriptional regulators (Hassig et al. Curr. Opin. Chem. Biol. 1997, 1, 300-308). The function of other proteins such as tubulin is also thought to be regulated by their acetylation state. HDACs participate in cellular pathways that control cell shape and differentiation, and an HDAC inhibitor has been shown effective in treating an otherwise recalcitrant cancer (Warrell et al. J. Natl. Cancer Inst. 1998, 90, 1621-1625). Eleven human HDACs, which use zinc as a cofactor, have been characterized (Taunton et al. Science 1996, 272, 408-411; Yang et al. J. Biol. Chem. 1997, 272, 28001-28007; Grozinger et al. Proc. Natl. Acad. Scl. U.S.A. 1999, 96, 4868-4873; Kao et al. Genes Dev. 2000, 14, 55-66; Hu et al. J. Biol. Chem. 2000, 275, 15254-15264; Mon et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 10572-10577; Venter et al. Science 2001, 291, 1304-1351). These members fall into three related classes (Class I, II, and IV) (Gregoretti et al., J. Mol. Biol. 2004, 338, 17-31). Class I HDACs include HDAC1, HDAC2, and HDAC3. Class II includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. Class II is further subdivided into Class IIa, which includes HDAC4, HDAC5, HDAC7, and HDAC9, and Class IIb, which includes HDAC6 and HDAC10. Class IV includes HDAC11. An additional Class of HDACs has been identified which use NAD as a cofactor. These have been termed Class III deacetylases, also known as the sirtuin deacetylases (SIRT1-7).
Class IIa enzymes (HDAC4, 5, 7, and 9) have been shown to have important regulatory functions in the body. To provide a few examples: HDAC9 has been recently shown to have important regulatory function in regulatory T cells, and that HDAC9 inhibitors seem highly desirable for the treatment of transplant patients as well as the treatment of autoimmune diseases (Tao et al. Nat. Med. 2007, 13, 1299-1307). HDAC7 inhibitors have been proposed for the treatment of life-threatening vascular diseases (Miano et al. Nat. Med. 2006, 12, 997-998), and HDAC5 inhibitors for the treatment of drug addiction (Nestler et al. Neuron 2007, 56, 517-529).
Based on this understanding of known HDACs, efforts are currently focused on developing novel HDAC inhibitors that are isoform- or class-specific inhibitors. Such specificity may allow for the development of pharmaceutical agents for the treatment of HDAC-associated diseases, with greater potency and/or decreased unwanted side effects based on greater on-target activity.